tbuckley/cabot-search huggingface dataset:
TMIC-07. MUTANT IDH-MEDIATED SUPPRESSION OF THE TH17 LINEAGE IN GLIOMA; BIOLOGIC IMPACT AND THERAPEUTIC POTENTIAL
Authors: Nathan Reynolds, Ashleigh Soedel, Emily Miller, David Ashley, Matthew Waitkus, Yiping He, Christopher Pirozzi
Journal: Neuro-Oncology (2023)

Abstract Great excitement has surrounded the identification of tumor-specific hotspot mutations in IDH1 as they are the first therapeutic targets of low grade gliomas that have been identified in the last several decades. With a low number of viable therapeutic targets, mutations in IDH1 represent new hope in treating these tumors that are invariably recurrent and confer a dismal prognosis in their aggressive forms. Additionally, mutations in IDH1 are tumor-specific suggesting their effective targeting can reduce the collateral damage to the normal brain imparted by standard therapies. Furthermore, mutations in IDH1 lead to the overproduction of D-2-hydroxyglutarate (D-2HG), which mediates many of mutant IDH1’s effects. To gain an understanding of mutant IDH-mediated tumorigenesis, we generated genetically faithful mouse models that harbor the pathognomonic signature including the IDH1-R132H mutation and p53 deletion. This model generates tumors that overproduce D-2HG, are histologically diffuse, and confer a prolonged survival compared to their wildtype counterparts. Additionally, these models display the proneural subtype and are enriched for an oligodendrocyte precursor cell gene expression signature, both of which are typified by IDH mutations in human glioma. Exploring the impact of the IDH mutation on the tumor microenvironment, we identified several diminished immune cell subsets among the mutant IDH murine tumors, including NK cells, monocytes, and M2 macrophages. Further analysis showed a reduced Th17 gene expression profile that was corroborated through in vitro studies. The biological impact of Th17 cells appears to be cancer-context dependent with only a few studies being performed in gliomas. With the potential for Th17-mediated anti-tumor activity, as observed in cases of melanoma, the prospect for elucidating a new therapeutic avenue is exciting. As such, the biological significance of D-2HG-mediated Th17 suppression, the underlying mechanism, as well as the therapeutic potential of Th17 restoration are actively being investigated.
TMIC-37. AN ADVANCED PHAGOCYTOSIS GLIOMA THERAPY BASED ON MICROGLIA: INSIGHT FROM AD THERAPY
Authors: Jie Lu, Yonggao Mou
Journal: Neuro-Oncology (2023)

Abstract INTRODUCTION Alzheimer's disease (AD) has an inverse correlation with glioma incidence. AD brain present a suppressive environment for glioma initiation and progression caused by amyloid β42 (Aβ42) activation of microglia. However, the underlying mechanisms remain elusive. METHODS Public database of patients with AD and brain cancer were collected and analyzed for the correlation between the two distinct diseases. The level of Aβ42 expression was examined by IHC staining in lower-grade glioma (LGG) and higher-grade glioma (HGG). Glioma-bearing mice were applied to evaluate the tumor suppressive effect induced by oligomer Aβ42 (OAβ42) in vivo. The co-culture system was applied to study the mechanism of OAβ42 activated microglia and enhanced tumor cell phagocytosis. RNA sequencing was performed to identify the underlying molecular mechanism involved in OAβ42 potentiated microglial phagocytosis. RESULTS OAβ42 is an innate peptide and a favorable prognostic biomarker of glioma with a prolonged OS in LGG than HGG (P=0.04). Injection of OAβ42 could inhibit the growth of glioma (P=0.0003) through enhancing microglial phagocytosis in the allogeneic mouse model. And the overall survival of the OAβ42 treated mice was longer than the vehicle group (P=.037). The OAβ42 primed microglia phagocytized more glioma cells than vehicle control in a co-culture system (P=0.0007). Autocrine of insulin-like growth factor 1(IGF-1) from OAβ42 activated microglia is essential for engulfing tumor cells. CONCLUSIONS Our findings proved OAβ42 modulated microglia could serve as a cellular target for treatment of glioma. Furthermore, our study provides a novel conceptual therapeutic strategy through modulating the function of existing immune cells in the microenvironment.
PATH-65. INTEGRATING DNA METHYLATION AND SEQUENCING TECHNOLOGIES FOR ADVANCED BRAIN TUMOR DIAGNOSIS
Authors: Kirsten Goebel, Daniel Schrimpf, Franziska Maria Ippen, Stefan M Pfister, David Jones, Wolfgang Wick, Andreas von Deimling, Felix Sahm, Abigail Suwala
Journal: Neuro-Oncology (2023)

Abstract DNA methylation has emerged as an indispensable tool in neuropathological diagnostics, improving the diagnosis of various brain tumor entities. At our institution, methylation arrays as well as DNA and RNA sequencing from Formalin-Fixed Paraffin-Embedded (FFPE) tissue blocks have become routine diagnostic practices for several years. In this study, we present an integration of DNA methylation analyses with targeted gene panel sequencing and RNA sequencing data in an extensive cohort comprising 5749 cases. The cohort encompassing both adult and pediatric patients with central nervous system (CNS) tumors. Only those cases conclusively classified by the Heidelberg brain tumor classifier (v12.5, cutoff &amp;gt; 0.9) and possessing available sequencing data were included in the analyses. The study includes several rare and less characterized brain tumor entities, unveiling frequent mutations and gene fusions that will improve the diagnostic process. Our study offers an unparalleled comprehensive overview of the prevalence of genetic alterations in brain tumors, precisely defined by their unique methylation classes. The profound implications of our results extend far beyond diagnosis alone, significantly augmenting the evaluation of targeted treatment options for patients undergoing DNA methylation analyses.
PATH-08. LONGITUDINAL MOLECULAR EVOLUTION OF IDH-WILDTYPE GLIOBLASTOMA IN ADULTS
Authors: Calixto-Hope Lucas, Nadeem Al-Adli, Jacob Young, Ramin Morshed, Rohit Gupta, Jasper Wu, Ajay Ravindranathan, Julieann Lee, Anny Shai, Nancy Ann Oberheim Bush, Jennie Taylor, John de Groot, Nicholas Butowski, Melike Pekmezci, Arie Perry, Andrew Bollen, Philip Theodosopoulos, Manish Aghi, Edward Chang, Shawn Hervey-Jumper, Joseph Costello, Jennifer Clarke, Aaron Diaz, Joanna Phillips, Mitchel Berger, Susan Chang, David Solomon
Journal: Neuro-Oncology (2023)

Abstract Glioblastoma, IDH-wildtype is a clinically and molecularly heterogeneous disease. To investigate how longitudinal molecular evolution drives tumor progression and treatment resistance, we performed comprehensive histopathologic, genomic, and epigenomic evaluation of paired initial and recurrent IDH-wildtype glioblastomas from 106 patients. The vast majority (96/106, 91%) demonstrated clonal genetic evolution and/or epigenetic subclass shifting between primary and recurrent tumors. This included oncogenic alterations initially present in a minute subclone that expanded to predominate at time of recurrence. 11% (12/106) developed hypermutation with a predominance of C &amp;gt; T transitions at time of recurrence secondary to the alkylating effects of temozolomide. In contrast, the remaining 9% (10/106) demonstrated nearly identical molecular signatures between the primary and recurrent tumors without additional acquired genetic drivers. We found that TERT promoter mutation and CDKN2A homozygous deletion were uniformly shared between initial and recurrent tumors, indicating that these are fundamental early events in gliomagenesis, whereas alterations involving EGFR, PDGFRA, PTEN, NF1, and TP53 were commonly among the events private to initial or recurrent tumors, indicating acquisition later during clonal evolution. Furthermore, we identified that 17% (18/106) of glioblastomas underwent sarcomatous transformation (i.e. “gliosarcoma”) at recurrence, which were highly enriched for NF1 inactivation and mesenchymal epigenetic subclass. Cell type deconvolution revealed an increased abundance of T-lymphocytes, tumor-associated macrophages, and neutrophils in NF1 inactivated glioblastomas. Together, our analyses demonstrate that most glioblastomas undergo longitudinal genomic and/or epigenomic evolution. While there is no predominant genetic event enriched in recurrent tumors, personalized genomic analysis at time of recurrence can reveal acquired treatment resistance mechanisms (e.g. EGFR variant switching, temozolomide-induced hypermutation, novel MGMT gene amplification) that may impact therapeutic decision making. As such, we believe that precision medicine treatment regimens for glioblastoma should be based on molecular studies performed on the most recent surgical specimen.
NIMG-37. FUNCTIONAL MRI AND DTI TRACTOGRAPHY AS ADJUNCTS TO IMPROVE THE PREDICTIVE VALUE OF TMS FOR CORTICAL LANGUAGE SITES
Authors: Matthew Muir, Sarah Prinsloo, Kyle Noll, Vinodh Kumar, Jeffrey Traylor, Sujit Prabhu
Journal: Neuro-Oncology (2023)

Abstract Surgeons must maximize the extent of resection while minimizing postoperative neurological morbidity in patients with eloquent gliomas. Transcranial magnetic stimulation (TMS) has emerged as a novel non-invasive technique to map the functional language cortex. However, multiple studies have documented the plethora of false positives that decrease the predictive value of TMS for intraoperative functional sites. Here we hypothesize that diffusion tensor imaging (DTI) tractography and functional magnetic resonance imaging (fMRI) can serve as adjuncts to identify true positive TMS preoperatively and increase the positive predictive value (PPV). We used a distortion correction algorithm to overlay the postoperative MRI with the preoperative surgical plan and correlated the resection versus preservation of certain structures with functional outcomes measured by pre to postoperative change in the Western Aphasia Battery (WAB) score in a cohort of 61 patients with language eloquent gliomas. We found that the resection of TMS points alone does not correlate with aphasic surgical deficits. We then seeded DTI tractography with TMS points and investigated the effect of progressively increasing fractional anisotropic (FA) thresholds. We found that the resection of TMS points with connecting white matter tracts identified at the 50%, 75%, and 85% FA thresholds strongly correlated with surgical deficits. (r=.38, p=.002; r=.61, p&amp;lt; .001, r=.54, p&amp;lt; .001) The PPV increased with increasing FA thresholds. The highest PPV was 50% at the 75% and 85% FA thresholds while the highest negative predictive value was 98% at the 75% FA threshold. We then combined fMRI with TMS and DTI tractography by only using fMRI-colocalized TMS points for tractography seeding. The PPV increased to 63% but the correlation coefficient with aphasic deficits stayed at .61. This study shows that adjunctive modalities can significantly increase the predictive value of TMS for preoperatively identifying true positive cortical sites of language function.
EXTH-39. D2C7-CAR: A NOVEL, DUAL-SPECIFIC CHIMERIC ANTIGEN RECEPTOR T CELL WITH HIGH SPECIFICITY FOR EGFR AND EGFRVIII IMPROVES SURVIVAL IN EGFR/EGFRVIII GLIOBLASTOMA AND EGFR OVER-EXPRESSING MEDULLOBLASTOMA
Authors: Zach Wilson, Daniel Wilkinson, Katherine Ryan, Vidya Chandramohan, Darrell Bigner, Peter Fecci
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND GBM is the most common primary malignant brain tumor found in adults. Despite strenuous efforts at improving outcomes, overall survival remains dismal (15-20 months). D2C7-CAR is a dual specific CAR T cell that targets EGFR and EGFRvIII. We performed pre-clinical analysis of D2C7-CAR glioblastoma and other EGFR aberrant tumor models to assessed efficacy and safety. METHODS U87 and U87vIII glioblastoma and DAOY medulloblastoma cell lines were characterized by flow cytometry to evaluate for EGFR and EGFRvIII expression. Cytotoxicity assays were performed utilizing flow cytometry on serially diluted effector: target ratios of U87, U87vIII, and DAOY mixed with D2C7 CAR. U87 and U87vIII was orthotopically implanted into the frontal lobe and DAOY was orthotopically implanted into the frontal lobe and posterior fossa of NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ (NSG) mice. After tumor implantation, D2C7 CAR, vIII CAR, or Mock CAR was introduced within the tumor bed. Survival was measured and analyzed using the Log-rank test. Bioluminescence with IVIS imaging of CT2AVIII with luciferase was utilized to perform time point analysis of IC tumor response to treatment vs control. Toxicity against somatic tissue EGFR expression was assessed by in vitro cytotoxicity assay as described above. RESULTS EGFR was detected in U87, U87vIII, and DAOY on flow analysis. EGFRvIII was expressed only on U87vIII. D2C7 CAR demonstrated effective in vitro cytotoxicity against all three cell lines with &amp;gt;90% cytotoxicity achieved at an effector: target ratio of 2.5:1. In vivo, D2C7 CAR significantly prolonged survival compared to treatment with mock and vIII CAR when tumor was implanted intracranially. Bioluminescence imaging demonstrated robust tumor response. D2C7 was not cytotoxic when co-cultured with EGFR expressing human keratinocytes. CONCLUSION D2C7-CAR demonstrates effective preclinical results both in vitro and in vivo. D2C7-CAR is not cytotoxic against human keratinocytes, suggesting it will be well tolerated in clinical trials.
SURG-35. SURVEY ASSESSMENT OF UTILITY IN THE PREOPERATIVE MAGNETIC RESONANCE (MR) TRACTOGRAPHY SURGICAL PLANNING
Authors: Mayur Sharma, Clark Chen
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND While tractography guided surgery is used by many surgeons as a matter of preference, there is controversy in the published literature as it relates to its clinical utility. The current literature consists of experiences of select surgeons. Here we adopted a survey-based approach with the goal of attaining a broader view of how tractography influence pre-operative planning in a sampling of practicing neurosurgeons. METHODS Three cases were prepared where the presence of a tumor distorted the optic radiation (case 1), the arcuate fasciculus (case 2), and corticospinal tract (case 3). This survey was administered at the Medtronic Cranial Consortium attended by twenty practicing neurosurgeons. To avoid commercial bias, we used both the Brainlab and the Medtronic platform to compute tractography. Each participant is asked to vote on a surgical trajectory prior to and after seeing the tractography images as well as whether tractography added value in validating their surgical approach. RESULTS In the three cases surveyed, 16-44% of the surgeons changed the surgical corridor selected after seeing the tractography images. The most common finding associated with a change in surgical corridor involved intersection of the surgical corridor with visualized tracts. Consistently, &amp;gt;80% of the surgeons surveyed felt that tractography added value in their surgical planning. These findings suggest tractography added value even in cases where the surgeon did not change their surgical approach, likely by confirming their prediction in the location of the pertinent tracts. CONCLUSION The clinical utility of tractography in pre-operative planning vary as a function of surgeon and the tumor anatomy, with &amp;gt; 80% of the participating consider that tractography added value in pre-operative surgical planning.
RADT-28. DISRUPTION OF BIOENERGETICS ENHANCES RADIO-SENSITIVITY OF PATIENT-DERIVED GLIOBLASTOMA TUMORSPHERES
Authors: HongGyu Yoon, Junseong Park, Seo Jin Kim, Jin-kyoung Shim, Eunhee Lee, Ran Joo Choi, Ju Hyung Moon, Eui-Hyun Kim, Seok-Gu Kang
Journal: Neuro-Oncology (2023)

Abstract INTRODUCTION Glioblastoma (GBM), the most common primary brain tumor, has been associated with poor prognosis despite various treatment modalities, the surgical resection accompanied by chemotherapy and radiotherapy. Although the importance of radiotherapy is well known, its combination with bioenergetics regulators has not been established in clinical practice. Here, we hypothesized that bioenergetics regulators improve the radio-sensitivity of GBM-tumorspheres (TS). METHODS Gene expression profiles of GBM patient-derived TSs were obtained from microarray. In vitro efficacies of the treatment were evaluated using clonogenic assay, 3D invasion assay, neurosphere-formation assay, and apoptosis-analysis. Protein expression was evaluated by western blot, and immunofluorescence was performed for detection of γH2AX foci. In vivo efficacies were confirmed using a mouse orthotopic-xenograft model. RESULTS GBM TSs with high-radioresistant or low-radioresistant were selected according to expression levels of radiation response associated genes. In order to select the bioenergetics regulators that significantly increased the radiotherapy effect of GBM-TSs, five bioenergetics regulators were combined which are oxidative-phosphorylation (OxPhos) inhibitor (IM156A), aldehyde-dehydrogenase inhibitor (gossypol) + OxPhos inhibitor (phenformin), fatty acid oxidation inhibitor (etomoxir), pentose-phosphate pathway inhibitor (dehydroepiandrosterone; DHEA) and glycolysis inhibitor (2-deoxy-D-glucose; 2DG). Amongst of these five bioenergetics regulators, DHEA and 2DG significantly augmented the therapeutic efficacies of ionizing radiation (IR) by reducing the survival fraction, stemness, and invasiveness in both high-radioresistant and low-radioresistant GBM TSs. IR combined with bioenergetics regulators (DHEA or 2DG) induced DNA damage response and apoptosis in low-radioresistant GBM TSs. In vivo experiments using a mouse orthotopic-xenograft model confirmed the tendency to prolong survival period and reduced the size in tumor after the combined treatment of 2DG with IR in low-radioresistant GBM TS. CONCLUSION These data proposes that the combination of bioenergetics regulators and radiotherapy is more effective than IR monotherapy itself. We expect that this combination regimen can strategically establish as a future treatment practice of GBM.
TMIC-06. GLIOBLASTOMA PROGRESSION IS PROMOTED BY C5AR1 SIGNALING THROUGH EMT INDUCTION, AND ITS BLOCKADE BY W54011 ATTENUATES MALIGNANT PHENOTYPES
Authors: Jihwan Yoo, Yoojung Oh, Dongkyu Lee, Seonah Choi, Eui-Hyun Kim, Ju Hyung Moon, Jong Hee Chang, Seok-Gu Kang
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Glioblastoma multiforme (GBM) is an aggressive brain tumor with poor prognosis. Tumor mesenchymal stem-like cells (tMSLCs) in GBM tissues secrete complement component 5a (C5a), which promotes tumor malignancy. This study aimed to investigate the impact of C5a on GBM tumorspheres (GBM-TS) and to evaluate the therapeutic potential of C5a inhibition using the C5a antagonist, W54011. METHODS RNA sequencing (RNAseq) was performed on tumor tissues to identify differentiaaly expressing genes (DEG) and perform gene set enrichment analysia (GSEA) to correlate with patient survival based on C5aR1 expression. GBM-TS and tMSLCs were cultured to create a conditioned medium (CM) containing C5a, which was used to stimulate GBM-TS. The effect of C5a on GBM-TS proliferation, invasion, and stemness was determined using WST/ATP assay, 3D invasion assay, and neurosphere formation assay. Western blot and RNAseq analysis were performed to validate the results. In vivo studies were conducted using orthotopic xenograft mouse models injected with GBM-TS alone or with CM and treated with W54011. RESULTS Patients with high C5aR1 expression had a poor prognosis. Treatment with CM increased proliferation, invasion, and stemness of GBM-TS, but W54011 reversed these effects. Treatment with CM induced epithelial-messenchymal transition (EMT) in GBM TSs, whereas W54011 restored the spherical morphology and induced apoptosis. Our results were supported by transcriptome analysis and marker expression in Western blots. In the orthotopic xenograft mouse model, co-injection of GBM-TS and CM resulted in larger tumors and poorer survival, while treatment with W54011 reduced tumor size. CONCLUSIONS C5a promotes the growth, invasion, and stemness of GBM-TS, and inhibition of C5a using W54011 may have therapeutic potential for patients with high C5a expression. These results provide insight into the underlying mechanisms of GBM progression and establish a knowledge base for the clinical efficacy of W54011 in GBM treatment.
CSIG-19. CANCER STEM CELL MEDIATED F11 DRIVES HYPER-THROMBOTIC ACTIVITY IN GLIOBLASTOMA
Authors: Anthony Sloan, Andrew Sloan, Alok Khorana, Craig Horbinski, Scott Cameron, Anirban Sen Gupta, Justin Lathia
Journal: Neuro-Oncology (2023)

Abstract Cancer-related thrombosis is the second leading cause of death for cancer patients and glioblastoma (GBM), the most common primary malignant brain tumor, is associated with approximately a 30% risk of venous thromboembolism, deep vein thrombosis, or pulmonary embolisms. While this remains a major clinical issue, the interaction between platelets and cancer cells has been underexplored in solid tumor models that do not metastasize, including GBM. GBM is a tumor which contains a high degree of cellular heterogeneity and has populations of therapeutically resistant cancer stem cells (CSCs) that drive tumor growth. Histologically CSCs are found in perivascular and pseudsopalisading regions of GBM, which are also areas of platelet localization. High platelet counts have been associated with poor clinical outcome in many cancers and while platelets are known to promote progression of other tumors. Our previous work demonstrated that CSCs co-opt and activate platelets to promote CSC growth by intrinsically producing thrombin via a cell intrinsic functional coagulation cascade. These findings provided further evidence that CSCs readily execute a highly liver-specific gene expression program that is mechanistically linked to GBM growth. We now demonstrate thrombin and platelet expression in GBM patient specimen creates a hyper-thrombotic GBM tumor-microenvironment. Further, genetic targeting of the CSC intrinsic coagulation cascade, via knockdown of coagulation factor 11 (F11), reduces CSC growth and tumor formation while also decreasing the ability for CSCs to activate platelets, subsequently decreasing the hyper-thrombotic state seen in GBM. Our observations suggest that CSCs execute a cell intrinsic coagulation mechanism to contribute to the hyper-thrombotic tumor-microenvironment seen in GBM and may shed light onto mechanisms of cancer associated thrombosis in not only GBM, but also other malignancies.